Adrenomedullin Signaling at the Maternal-Fetal Interface

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 DESCRIPTION (provided by applicant): Adrenomedullin (AM) is a multifunctional peptide that is involved in a variety of biological processes, including embryonic development, angiogenesis, cardio-protection, and innate immunity. Maternal plasma levels of AM rise substantially during a normal pregnancy, but abnormally low levels are often associated with a variety of pregnancy complications including preeclampsia, fetal growth restriction, gestational diabetes and spontaneous abortion. Using genetically engineered mouse models, our laboratory was the first to demonstrate that haploinsufficiency for maternal AM causes a multitude of reproductive defects associated with abnormal implantation and fetal growth restriction. We also revealed that fetal-derived AM is required for the appropriate remodeling of maternal spiral arteries-a novel demonstration of the importance of fetal-to-maternal communication during pregnancy. Collectively our studies have shown that the dosage and signaling of AM peptide at the maternal-fetal interface is an essential aspect to ensuring a normal pregnancy and birth. Therefore, we intend to build on these findings by asking: "How and why does the dosage of AM get precisely regulated at the maternal-fetal interface?" Using sophisticated genetic mouse models and in vitro pharmacological and cell biological assays, we plan to address this broad question in three discrete Aims. In Specific Aim 1, we will test the hypothesis that the newly characterized decoy chemokine receptor, CXCR7, acts as a "biological rheostat" for AM-mediated activity during early implantation and placentation. Specific Aim 2 will test the hypothesis that the dosage of AM gene expression in fetal trophoblast cells is balanced by a discrete subset of cell-intrinsic miRNAs that are induced by maternal factors such as pregnancy hormones and environmental factors, like cigarette smoke. In Specific Aim 3 we will further elucidate the distinct cellular process and molecular mechanisms that govern the effects of AM on spiral artery (SA) remodeling. Results from our studies will further our basic understanding of molecules and processes that govern maternal- to-fetal communication in the placenta and have the potential of providing new clinical diagnostic tools and therapeutic approaches for the amelioration of complications of pregnancy.